Immunotherapy refers to modulating a person's immune responses to impart a desirable therapeutic effect. Immunotherapeutics refer to those compositions which, when administered to an individual, modulate the individual's immune system sufficient to ultimately decrease symptoms which are associated with undesirable immune responses or to ultimately alleviate symptoms by increasing desirable immune responses. In some cases, immunotherapy is part of a vaccination protocol in which the individual is administered a vaccine that exposes the individual to an immunogen against which the individual generates an immune response in such cases, the immunotherapeutic increases the immune response and/or selectively enhances a portion of the immune response (such as the cellular arm or the humoral arm) which is desirable to treat or prevent the particular condition, infection or disease.
In designing vaccines, it has been recognized that vaccines that produce the target antigen in cells of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use avirulent vectors and DNA vaccines each lead to the production of antigens in the cell of the vaccinated individual which results in induction of the cellular arm of the immune system. On the other hand, killed or inactivated vaccines, and sub-unit vaccines which comprise only proteins do not induce good cellular immune responses although they do induce an effective humoral response.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines that produce the target antigen in cells of the vaccinated individual such as live attenuated vaccines, recombinant vaccines that use avirulent vectors and DNA vaccines are often preferred.
There is a need for vaccine approaches that can induce strong T cell and B cell immunity in humans. Recent concerns over attenuation, vaccine manufacturing complexity, serological interference, as was observed in the HIV STEP trial, among a host of other issues serve to underscore this important issue. In non-human primate models and in human clinical trials, simple plasmid DNA as a vaccine platform has not induced levels of immunogenicity satisfactory for commercial development efforts to be supported. In head to head comparisons some naked plasmid-based vaccines did not induce either cellular or humoral responses comparable to those induced by their viral vector counterparts, including the commonly used adenovirus serotype 5 (Ad5) platform.
The development of DNA vaccine technology as a stand-alone method of vaccination, as well as its utility in current prime-boost platforms, would benefit by the development of strategies to enhance its immune potency. The manipulation of codon and RNA encoding sequences as well as changes in leader sequences have been reported to enhance the expression of plasmid-encoded immunogens. In addition, the creation of consensus immunogens attempts to address the need for broad immunological coverage to account in part for viral diversity.
In addition, other strategies have been employed that focus on improving the physical delivery of DNA plasmids by improving formulations and device driven technologies. DNA vaccines delivered by electroporation (EP) have been reported to enhance antigen-specific interferon-γ (IFNγ) production following immunization of plasmid DNA in rhesus macaques.
The co-delivery of plasmid-encoded molecular adjuvants to augment vaccine-induced responses is another important area of this specific investigation. One of the best-characterized molecular adjuvants in non-human primates is IL-12, a TH1 polarizing cytokine that drives CTL responses by providing the “third signal” needed for efficient activation and antigen-specific expansion of naive CD8+T cells. IL-12 is a heterodimer which contains two subunits, p35 and p40. It has been shown to be the most impressive immune enhancing cytokine, particularly for driving CD8 T cells when engineered as a DNA vaccine. In macaques, IL-12 has been shown to be an adjuvant that is highly potent for expanding the cellular Immune potency of a DNA vaccine targeting multiple antigens. In both macaques as well and in humans such a DNA vaccine adjuvant can significantly improve the immune responses induced by a DNA vaccine.
U.S. Pat. No. 5,723,127, which is incorporated herein by reference, discloses IL-12 as a vaccine adjuvant. PCT application no. PCT/US1997/019502 and corresponding U.S. application Ser. No. 08/956,865, which is incorporated herein by reference, discloses DNA vaccines and DNA constructs comprising IL-12 coding sequences.
There remains a need for improved vaccines and immunotherapeutics. There is a need for compositions and methods that produce enhanced immune responses. Likewise, while some immunotherapeutics are useful to modulate immune response in a patient there remains a need for improved immunotherapeutic compositions and methods. There remains a need for improved constructs which encode IL-12 and can be used as part of DNA vaccine strategies. There remains a need for improved constructs which encode IL-12 and can be used as an immunotherapeutic. There remains a need for improved constructs which encode IL-12 and can be used to achieve high levels of expression of IL-12.